EP0070013B1 - Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group - Google Patents

Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group Download PDF

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EP0070013B1
EP0070013B1 EP82106172A EP82106172A EP0070013B1 EP 0070013 B1 EP0070013 B1 EP 0070013B1 EP 82106172 A EP82106172 A EP 82106172A EP 82106172 A EP82106172 A EP 82106172A EP 0070013 B1 EP0070013 B1 EP 0070013B1
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Prior art keywords
carboxylic acid
dioxolen
methyl
alkyl
oxo
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EP0070013A1 (en
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Christensen G. Burton
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Merck and Co Inc
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/32—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D317/34—Oxygen atoms
    • C07D317/40—Vinylene carbonate; Substituted vinylene carbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/88—Compounds with a double bond between positions 2 and 3 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • This invention provides a novel moiety wherein R is alkyl of 1-6 carbon atoms, especially methyl or t-butyl; which when present as an ester of a carboxylic acid, i.e. cefoxitin, methyldopa or 2-(ethylthio)-6[3-(1-R-hydroxyethyl)-penem-3-carboxylic acid, enhances oral absorbability of the ester product.
  • R is alkyl of 1-6 carbon atoms, especially methyl or t-butyl; which when present as an ester of a carboxylic acid, i.e. cefoxitin, methyldopa or 2-(ethylthio)-6[3-(1-R-hydroxyethyl)-penem-3-carboxylic acid, enhances oral absorbability of the ester product.
  • EP-A-39086 refers to (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methylesters of ampicillin.
  • the useful esters of this invention are prepared by utilizing the alcohol or halide, e.g. chloride or bromide form of group I above in reaction with the free acid or salt form of the desired pharmaceutically active compound of which enhanced oral absorption is desired.
  • the bromide form: (the 5-methyl compound is prepared as described by H. Scherf and H. Plum, Liebiegs Ann, Chem., 1977, 27-32, and the other 5-alkyls, including 5-t-butyl, are prepared in a similar fashion) is reacted with either the lithium or silver salt form of the pharmaceutical acid.
  • Preferable reaction conditions include a ratio of from about equivalent to twice equivalent amounts of Compound II to the pharmaceutical acid, in a solvent such as hexamethylphosphoramide, dimethylformamide, acetonitrile, dimethyl sulfoxide, or the like, at from about 0-50°C, preferably about 25-35°C, for from 2-24 hours, (the reaction proceeds more quickly at the higher end of the range).
  • a solvent such as hexamethylphosphoramide, dimethylformamide, acetonitrile, dimethyl sulfoxide, or the like
  • the ester can be recovered in from 10-60% yield, and is purified by recrystallization in an appropriate solvent system, such as ethylacetate-diethyl ether.
  • the solution is added to a stirred mixture of 5 liters of water and 5 liters of ethyl acetate.
  • the separated aqueous phase is extracted with 2x2 liters of ethyl acetate, and the combined solution is washed with 2x2 liters of water and 1 x2 liters of saturated sodium chloride solution.
  • the solution is dried over anhydrous magnesium sulfate, treated with 15 g of Darco G-60, (activated charcoal), and after filtration, concentrated under vacuum at room temperature.
  • the concentrate is dissolved in 270 ml of methylene chloride, and the resulting solution added slowly to 13 liters of petroleum-benzin with rapid stirring.
  • the precipitate is filtered off, washed with petroleum-benzin and dried at r.t./0.1 mm/18 hrs./P z O s .
  • the above impure ester is dissolved in 400 ml of ethyl acetate at room temperature.
  • the solution is treated with 2x7.0 g of Darco G-60, washing the charcoal cake well after each treatment with ethyl acetate.
  • the combined filtrate and washes are concentrated at room temperature at 2-5 mm to a volume of about 500 ml.
  • To the stirred concentrated solution under anhydrous conditions is added slowly 700 ml of ethyl ether to the point of producing a first permanent cloudiness.
  • the solution is clarified with a few drops of ethyl acetate and then ether (ca 5 ml) is carefully added to cloudiness again.
  • the silver salt of cefoxitin can be prepared by reacting 1 equivalent of cefoxitin free acid with 1 equivalent sodium bicarbonate in water then adding the resulting solution to a solution of 2 equivalents of silver nitrate in aqueous solution.
  • the silver salt precipitates, is dried and used as the starting material in reaction with the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide, as described above, as a suspension in anhydrous acetonitrile.
  • the final product, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of cefoxitin can be administered to humans at the usual dosage levels and regimen as cefoxitin sodium, a widely available product.
  • the product can be given IV or orally, at levels of 2-20 mg/kg/day. Blood levels of drug are enhanced in comparison with cefoxitin sodium.
  • methyldopa and 2-(ethy)thio)-6p-(1R-hydroxyethyi)-penem-3-carboxyiic acid can have enhanced blood levels, if they are employed in the form of the (5-alkyl-2-oxo-1,3-dioxolen-4-yl)-methyl ester.
  • the ester form of these compounds is prepared using the same general procedure described above for the cefoxitin ester.
  • Cefoxitin methyldopa and 2-(ethylino)-6(3-(1R-hydroxyethyl)-penem-3-carboxylic acid are known in the art as pharmaceuticals in the acid or sodium salt form.
  • Their dosage form, dosage regimen and indications as the (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is the same as the free acid or pharmaceutically accepted salt or ester forms already published.
  • the advantage of the ester group yields enhanced blood levels of the active compound in the human or animal being treated.
  • the ethyl acetate extract is washed with two 10 mL portions of water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated at 40°C and 15 mm. The residue is dried further at 20-25°C and 0.1 mm to give 6.5 g of the N-t-BOC derivative of methyldopa.
  • the ethyl acetate extract is washed with water saturated with sodium chloride, 10 mL, dried over anhydrous sodium sulfate, filtered and concentrated at 40-45°C and 15 mm.
  • the ester base is converted to the (2R, 3R) hydrogen tartrate hemihydrate salt, 370 mg, mp 123-128°C dec, with L-tartaric acid in a 95% ethanol-ethyl acetate solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Description

    Summary of the invention
  • This invention provides a novel moiety
    Figure imgb0001
    wherein R is alkyl of 1-6 carbon atoms, especially methyl or t-butyl; which when present as an ester of a carboxylic acid, i.e. cefoxitin, methyldopa or 2-(ethylthio)-6[3-(1-R-hydroxyethyl)-penem-3-carboxylic acid, enhances oral absorbability of the ester product.
  • EP-A-39086 refers to (5-methyl-2-oxo-1,3-dioxolen-4-yl)-methylesters of ampicillin.
  • The use of 1,3-dioxolen-2-one derivatives as modifiers for prodrugs preparation is known from EP-A-39477. The only pharmaceutically active compound mentioned in this reference is ampicillin:
  • The useful esters of this invention are prepared by utilizing the alcohol or halide, e.g. chloride or bromide form of group I above in reaction with the free acid or salt form of the desired pharmaceutically active compound of which enhanced oral absorption is desired. Preferably, the bromide form:
    Figure imgb0002
    (the 5-methyl compound is prepared as described by H. Scherf and H. Plum, Liebiegs Ann, Chem., 1977, 27-32, and the other 5-alkyls, including 5-t-butyl, are prepared in a similar fashion) is reacted with either the lithium or silver salt form of the pharmaceutical acid.
  • Preferable reaction conditions include a ratio of from about equivalent to twice equivalent amounts of Compound II to the pharmaceutical acid, in a solvent such as hexamethylphosphoramide, dimethylformamide, acetonitrile, dimethyl sulfoxide, or the like, at from about 0-50°C, preferably about 25-35°C, for from 2-24 hours, (the reaction proceeds more quickly at the higher end of the range).
  • The ester can be recovered in from 10-60% yield, and is purified by recrystallization in an appropriate solvent system, such as ethylacetate-diethyl ether.
  • The preparation of the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of cefoxitin illustrates one embodiment of this invention.
    • Example 1 Step A. Preparation of cefoxitin lithium salt
  • To a stirred suspension of 42.75 g (0.1 m) of cefoxitin in 1 liter of water is added at 0-5° over a period of 45-60 minutes a solution of 0.1 N lithium hydroxide. The initial pH of the mixture is about 3.0. Addition of the alkaline solution is so regulated that the pH does not rise above 5.5. The solution, about 2.5 liters, is filtered to remove a small amount of undissolved free acid and then subdivided in equal portions into 5x5 liter round bottom flasks for lyophilization and for use in the next steps.
    • Step B. Esterification
  • Fifty-four grams (0.125 m) of cefoxitin Li salt is charged into a 3-liter, 3-necked round bottom flask, fitted with a stirrer and Drierite tube. The solid is stirred and 540 ml of hexamethylphosphoramide (HMPA), pH 6.7, is added. Upon the addition of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide, (0.25 m), the temperature rises slightly, and is kept at about room temperature, while stirring 20 minutes. Esterification is monitored by tlc (silica gel plates, ethylacetate-chloroform solvent).
  • After the end of the reaction period, the solution is added to a stirred mixture of 5 liters of water and 5 liters of ethyl acetate. The separated aqueous phase is extracted with 2x2 liters of ethyl acetate, and the combined solution is washed with 2x2 liters of water and 1 x2 liters of saturated sodium chloride solution. The solution is dried over anhydrous magnesium sulfate, treated with 15 g of Darco G-60, (activated charcoal), and after filtration, concentrated under vacuum at room temperature. The concentrate is dissolved in 270 ml of methylene chloride, and the resulting solution added slowly to 13 liters of petroleum-benzin with rapid stirring. The precipitate is filtered off, washed with petroleum-benzin and dried at r.t./0.1 mm/18 hrs./PzOs.
    • Step C. Purification
  • The above impure ester is dissolved in 400 ml of ethyl acetate at room temperature. The solution is treated with 2x7.0 g of Darco G-60, washing the charcoal cake well after each treatment with ethyl acetate. The combined filtrate and washes are concentrated at room temperature at 2-5 mm to a volume of about 500 ml. To the stirred concentrated solution under anhydrous conditions is added slowly 700 ml of ethyl ether to the point of producing a first permanent cloudiness. The solution is clarified with a few drops of ethyl acetate and then ether (ca 5 ml) is carefully added to cloudiness again. After stirring for a few minutes, the solution is allowed to stand undisturbed at room temperature for 3-4 hours, and then aged at 5° overnight. The mixture is filtered, and the solid washed with 3x50 ml of ether. The cefoxitin ester is dried at r.t./0.1 mm/P205/24 hours.
  • Alternatively, the silver salt of cefoxitin can be prepared by reacting 1 equivalent of cefoxitin free acid with 1 equivalent sodium bicarbonate in water then adding the resulting solution to a solution of 2 equivalents of silver nitrate in aqueous solution. The silver salt precipitates, is dried and used as the starting material in reaction with the (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide, as described above, as a suspension in anhydrous acetonitrile.
  • The final product, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of cefoxitin can be administered to humans at the usual dosage levels and regimen as cefoxitin sodium, a widely available product. The product can be given IV or orally, at levels of 2-20 mg/kg/day. Blood levels of drug are enhanced in comparison with cefoxitin sodium.
  • Furthermore, methyldopa and 2-(ethy)thio)-6p-(1R-hydroxyethyi)-penem-3-carboxyiic acid can have enhanced blood levels, if they are employed in the form of the (5-alkyl-2-oxo-1,3-dioxolen-4-yl)-methyl ester. The ester form of these compounds is prepared using the same general procedure described above for the cefoxitin ester.
  • Cefoxitin methyldopa and 2-(ethylino)-6(3-(1R-hydroxyethyl)-penem-3-carboxylic acid are known in the art as pharmaceuticals in the acid or sodium salt form. Their dosage form, dosage regimen and indications as the (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester is the same as the free acid or pharmaceutically accepted salt or ester forms already published. The advantage of the ester group yields enhanced blood levels of the active compound in the human or animal being treated.
    • Example 2 Preparation of (4-methyl-1,3-dioxol-2-one-5-yl-methyl) ester of methyldopa Step A. (S)N-(t-Butylcarbonyl)-3-hydroxy-α-methyl-tyrosine
  • A mixture of (S) 3-hydroxy-a-methyltyrosine sesquihydrate [methyldopa] (5.0 g, 21 mmol), triethylamine (2.1 g, 21 mmol) and di t-butyl dicarbonate (4.9 g, 23 mmol) in dimethylformamide, 50 mL, is stirred at 20-25°C for 1 hour and then at 60°C for 18 hours under nitrogen. After removing most of the dimethylformamide at 50-60°C and 0.1 mm, the residue is partitioned between a 5% citric acid solution, 25 mL, and ethyl acetate, 75 mL. The ethyl acetate extract is washed with two 10 mL portions of water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated at 40°C and 15 mm. The residue is dried further at 20-25°C and 0.1 mm to give 6.5 g of the N-t-BOC derivative of methyldopa.
    • Step B. 4-Methyl-1,3-dioxol-2-one-5-ylmethyl(S)N-(t-Butoxycarbonyl)-3-hydroxy-α-methyltyrosinate
  • A solution of N-(t-butoxycarbonyl)-3-hydroxy-a-methyltyrosine (760 mg, 2.44 mmol), triethylamine (263 mg, 2.60 mmol) and 4-bromomethyl-5-methyl-1,3-dioxol-2-one (500 mg, 2.60 mmol) in dimethylformamide, 10 mL, is stirred at 60°C for 3 hours under nitrogen. Most of the dimethylformamide is removed at 50-60°C and 0.1 mm and the residue is partitioned between saturated sodium bicarbonate solution, 10 mL, and ethyl acetate, 50 mL. The ethyl acetate extract is washed with water saturated with sodium sulfate, filtered and concentrated at 40-45°C and 15 mm. Flash chromatography of the residue over 40 g of silica gel 60 (230-400 mesh) with 3% methanol-97% chloroform as eluent affords 320 mg of the desired ester.
    • Step C. 4-Methyl-1,3-dioxol-2-one-5-ylmethyl(S)3-Hydroxy-α-methyltyrosinate (2R, 3R) hydrogentartrate hemihydrate
  • A solution of 4-methyl-1,3-dioxol-2-one-5-ylmethyl (S)N-(t-butoxycarbonyl)-3-hydroxy-a-methyl- tyrosinate (1.24 g, 2.93 mmol) in ethyl acetate, 40 mL is cooled in an ice bath and saturated with anhydrous hydrogen chloride for 10 min. The solution is allowed to warm slowly to 20-25°C over 1.5 hours and then concentrated at 30-40°C and 15 mm. The residue is treated with a saturated sodium bicarbonate solution, 10 mL, and the deblocked ester is extracted into ethyl acetate, 50 mL. The ethyl acetate extract is washed with water saturated with sodium chloride, 10 mL, dried over anhydrous sodium sulfate, filtered and concentrated at 40-45°C and 15 mm. The ester base is converted to the (2R, 3R) hydrogen tartrate hemihydrate salt, 370 mg, mp 123-128°C dec, with L-tartaric acid in a 95% ethanol-ethyl acetate solution.
    • Calc. for C15H17NO7.C4H6O6.1/2 H20: C, 47.30; H, 5.01; N, 2.90
    • Found: C, 47.34; H, 5.05; N, 289
  • The compound (4-t-butyl-1,3-dioxol-2-one-5-yl)methyl ester of methyldopa, as well as other 4-lower alkyl compounds, can be prepared in a similar fashion using analogous reactants. An example follows:
    • Example 3
  • Preparation of 4-t-butyl-1,3-dioxol-2-one-5-ylmethyl (S)-3-hydroxy-a-methyl tyrosinate (2R, 3R) hydrogentartrate hemihydrate
    • Step A. 5-t-Butyl-4-methyl-1,3-dioxolen-2-one
  • Forty-four g of a 12.5% solution of phosgene in toluene is added over 30 min to a well stirred solution of 4,4-dimethyl-2-hydroxy-3-pentanone (4.85 g, 37.3 mmol) in toluene, 90 ml, at 0-5°C. Following this addition, a solution of pyridine, 11.4 ml, in toluene, 25 ml, is then added to the cooled reaction mixture over 30 min. After stirring at 20-25°C for 20 hours, the reaction mixture is washed with 3N HCI and water saturated with NaCl. The toluene extract is dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. After addition of p-toluenesulfonic acid hydrate, 100 mg, to the residue, it is stirred neat at 160°C for 24 hours. The resulting black liquid is dissolved in ethyl acetate, washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtering and concentrating under reduced pressure, the residue is distilled to give 3.5 g of product, bp 82-4°C at 3 mm.
    • Step B. 4-Bromomethyl-5-t-butyl-1,3-dioxolen-2-one
  • A mixture of 4-methyl-5-t-butyl-1,3-dioxolen-2-one (3.5 g, 22.4 mmol), N-bromosuccinimide (4.16 g, 23.4 mmol) and dibenzoylperoxide (20 mg) in carbon tetrachloride (100 ml) is stirred at reflux for one hour. After filtering, the filtrate is concentrated under reduced pressure to give the 4-bromomethyl derivative as an oil.
    • Step C. 4-t-Butyl-1 ,3-dioxol-2-one-5-ylmethyl (S)3-hydroxy-α-methyltyrosinate (2R,3R) hydrogentartrate hemihydrate
  • A mixture of 4-bromomethyl-5-t-butyl-1,3-dioxolen-2-one (5.27 g, 22.4 mmol) and (S)3-hydroxy-a-methyltyrosine sesquihydrate (5.3 g, 22.4 mmol) in dry dimethylformamide (35 ml) is stirred at 20-25°C for three hours under nitrogen. Solvent is removed at 40-50°C and 0.1-0.3 mm pressure and the residue is partitioned between a saturated aqueous sodium bicarbonate solution and ethyl acetate. The ethyl acetate extract is washed with water saturated with sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. The crude ester is converted to the (2R, 3R) hydrogen tartrate salt and recrystallized from an 95% ethanol-ethyl acetatehexane mixture to give 6.75 g (57.4%) of the desired ester as the hydrogentartrate hemihydrate salt, mp=113-121°C, slow decomposition.
    • Anal. Calcd. for C18H23NO7.C4H6O6.1/2 H20: C 50.38, H, 5.77, N, 2.67
    • Found: C, 50.40, H, 5.85; N, 2.54

Claims (4)

1. A process for preparing the (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester of a carboxylic acid wherein alkyl has 1-6 carbon atoms and wherein the carboxylic acid is cefoxitin, methyldopa or 2-(ethylthio)-6β-(lR-hydroxyethyl)-penem-3-carboxylic acid, comprising reacting a compound having the formula
Figure imgb0003
wherein R is alkyl of 1-6 carbon atoms and R' is OH or halogen with the free acid or a salt form of cefoxitin, methyldopa or 2-(ethylthio)-6(3-(1R-hydroxyethyl)-penem-3-carboxylic acid.
2. The process of claim 1 wherein R' is Br or CI and the carboxylic acid is in the salt form, preferably the lithium or silver salt.
3. The process of claims 1 or 2 for preparing 4-t-butyl-1,3-dioxol-2-one-5-ylmethyl(S)-3-hydroxy-α-methyltyrosinate (2R, 3R) hydrogentartrate, and that being in the hemihydrate form.
4. The process of claims 1 or 2 for preparing 4-methyl-1,3-dioxol-2-one-5-ylmethyl(S)-3-hydroxy-α-methyltyrosinate (2R, 3R) hydrogentartrate, and that being in the hemihydrate form.
EP82106172A 1981-07-13 1982-07-12 Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group Expired EP0070013B1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT82106172T ATE22895T1 (en) 1981-07-13 1982-07-12 ENHANCEMENT OF ORAL ABSORPTION OF CARBOXYL ACID PHARMACEUTICALS THROUGH FORMATION OF THE (5- ALKYL-2-OXO-1,3-DIOXOLEN-4-YL)-METHYLESTERS.

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
US28282181A 1981-07-13 1981-07-13
US282821 1981-07-13
US28517081A 1981-07-18 1981-07-18
US285170 1981-07-20
US32472881A 1981-11-25 1981-11-25
US34441382A 1982-02-01 1982-02-01
US344413 1982-02-01
US36603682A 1982-04-06 1982-04-06
US366036 1982-04-06
US324728 2002-12-19

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EP0070013A1 EP0070013A1 (en) 1983-01-19
EP0070013B1 true EP0070013B1 (en) 1986-10-15

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EP (1) EP0070013B1 (en)
CA (1) CA1202020A (en)
DE (1) DE3273786D1 (en)
DK (1) DK312182A (en)
GR (1) GR76525B (en)
IE (1) IE53425B1 (en)
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US4874856A (en) * 1985-06-24 1989-10-17 Bristol-Myers Company 3-(substituted)propenyl-7-(aminothiazolylacetamido) ceph-3-em-4-carboxylic acids and esters thereof
JPS6341475A (en) * 1986-08-07 1988-02-22 Mikasa Seiyaku Kk Novel arylacetic acid derivative
DE3731085A1 (en) * 1987-09-16 1989-04-06 Hoechst Ag NEW AMINO ACID ESTERS, METHOD FOR THE PRODUCTION THEREOF, MEDICINAL PRODUCTS CONTAINING THEM AND THE USE THEREOF
WO2024104331A1 (en) * 2022-11-14 2024-05-23 江苏恒瑞医药股份有限公司 Prodrug of levodopa

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039477A1 (en) * 1980-04-30 1981-11-11 Kanebo, Ltd. Use of 1,3-Dioxolen-2-one derivatives

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CA1212105A (en) * 1980-04-30 1986-09-30 Shoji Ikeda Ampicillin esters and production thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039477A1 (en) * 1980-04-30 1981-11-11 Kanebo, Ltd. Use of 1,3-Dioxolen-2-one derivatives

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PT75228B (en) 1985-11-11
EP0070013A1 (en) 1983-01-19
DE3273786D1 (en) 1986-11-20
DK312182A (en) 1983-01-14
GR76525B (en) 1984-08-10
IE53425B1 (en) 1988-11-09
IE821669L (en) 1983-01-13
CA1202020A (en) 1986-03-18

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